Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000189757 | SCV000243405 | pathogenic | not provided | 2012-04-12 | criteria provided, single submitter | clinical testing | p.Gly77Arg (GGA>CGA): c.229 G>C in exon 3 in the TPP1 gene (NM_000391.3) has been reported previously in association with late-infantile neuronal ceroid lipofuscinosis (LINCL) (Sleat et al., 1999). The Gly77Arg mutation alters a highly conserved position in the pro-segment of the TPP1 protein, and in vitro functional studies indicate that this mutation impairs protein folding and significantly reduces TPP1 enzyme activity (Walus et al., 2010). We interpret G77R as a disease-causing mutation. The variant is found in EPILEPSY panel(s). |
Counsyl | RCV000673684 | SCV000798914 | likely pathogenic | Neuronal ceroid lipofuscinosis 2 | 2018-03-29 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000189757 | SCV001576806 | pathogenic | not provided | 2023-07-20 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects TPP1 function (PMID: 18411270, 20340139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 207567). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 10330339, 30119717, 30771299, 31741823). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 77 of the TPP1 protein (p.Gly77Arg). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001731509 | SCV001983463 | pathogenic | Neuronal ceroid lipofuscinosis | 2021-09-27 | criteria provided, single submitter | clinical testing | Variant summary: TPP1 c.229G>C (p.Gly77Arg) results in a non-conservative amino acid change located in the activation domain (IPR015366) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, the variant is located to the last nucleotide of exon 3, therefore it can also affect splicing. Computational tools predict a significant impact on normal splicing: 2 predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250960 control chromosomes (gnomAD). The variant, c.229G>C, has been reported in the literature, in compound heterozygous- and homozygous state, in at least three individuals who were affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Retterer_2015, Nickel_2018, Jilani_2019, Lukacs_2019, Dozieres-Puyravel_2020, Estublier_2020, Kovacs_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating the protein level effect of the variant (i.e. expressing it from an intronless cDNA construct), and demonstrated very low residual enzyme activity and altered intracellular trafficking in a mammalian cell system (Walus_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |